tbuckley/cabot-search huggingface dataset:
A major role for CD4+ T cells in driving cytokine release syndrome during CAR T cell therapy
Authors: Morgane Boulch, Marine Cazaux, Alexis Cuffel, Mathilde Ruggiu, Vincent Allain, Béatrice Corre, Yann Loe-Mie, Benoit Hosten, Salvatore Cisternino, Sylvain Auvity, Catherine Thieblemont, Sophie Caillat-Zucman, Philippe Bousso
Journal: Cell Reports Medicine (2023)

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy represents a breakthrough for the treatment of B cell malignancies. Yet, it can lead to severe adverse events, including cytokine release syndrome (CRS), which may require urgent clinical management. Whether interpatient variability in CAR T cell subsets contributes to CRS is unclear. Here, we show that CD4+ CAR T cells are the main drivers of CRS. Using an immunocompetent model of anti-CD19 CAR T cell therapy, we report that CD4+, but not CD8+, CAR T cells elicit physiological CRS-like manifestations associated with the release of inflammatory cytokines. In CAR T cell-treated patients, CRS occurrence and severity are significantly associated with high absolute values of CD4+ CAR T cells in the blood. CRS in mice occurs independently of CAR T cell-derived interferon γ (IFN-γ) but requires elevated tumor burden. Thus, adjusting the CD4:CD8 CAR T cell ratio to patient tumor load may help mitigate CAR T cell-associated toxicities.
Absorbable implants in sport medicine and arthroscopic surgery: A narrative review of recent development
Authors: Boxuan Huang, Ming Yang, Yuhui Kou, Baoguo Jiang
Journal: Bioactive Materials (2023)

Over the past two decades, advances in arthroscopic and minimally invasive surgical techniques have led to significant growth in sports medicine surgery. Implants such as suture anchors, interference screws, and endo-buttons are commonly used in these procedures. However, traditional implants made of metal or inert materials are not absorbable, leading to complications that affect treatment outcomes. To address this issue, absorbable materials with excellent mechanical properties, good biocompatibility, and controlled degradation rates have been developed and applied in clinical practice. These materials include absorbable polymers, absorbable bioceramics, and absorbable metals. In this paper, we will provide a comprehensive summary of these absorbable materials from the perspective of clinicians, and discuss their clinical applications and related research in sport medicine.
Spatial transcriptomic profiling reveals the pathophysiology of early-stage hidradenitis suppurativa
Authors: Christine Suh-Yun Joh, Soyoung Jeong, Cheol Lee, Hee Jung Lee, Jung Ho Lee, Hyun Seung Choi, Soyun Cho, Gwangil Kim, Jaehwan Kim, James G Krueger, Chung-Gyu Park, Jung U Shin, Seon-Pil Jin, Hyun Je Kim
Journal: British Journal of Dermatology (2023)

We investigated the role of the epithelium of nodules in Hurley stage I hidradenitis suppurativa (HS) by using spatial transcriptomics to analyse the profiles of epithelial cells and dermal-infiltrating immune cells. Compared with epidermal cysts, genes related to bacterial response, inflammatory mediators and neutrophil degranulation pathways were upregulated in the epithelial cells of early-stage HS nodules. Our analysis of dermal-infiltrating immune cells surrounding the epithelium of nodules revealed significantly elevated levels of B-cell-related genes. Similarly to the sinus tract formation observed in moderate-to-severe HS, we propose that the production of inflammatory mediators in early-stage HS may involve the activation of keratinocytes and their interaction with dermal-infiltrating immune cells.
Sequence dependencies and mutation rates of localized mutational processes in cancer
Authors: Gustav Alexander Poulsgaard, Simon Grund Sørensen, Randi Istrup Juul, Morten Muhlig Nielsen, Jakob Skou Pedersen
Journal: Genome Medicine (2023)

Cancer mutations accumulate through replication errors and DNA damage coupled with incomplete repair. Individual mutational processes often show nucleotide sequence and functional region preferences. As a result, some sequence contexts mutate at much higher rates than others, with additional variation found between functional regions. Mutational hotspots, with recurrent mutations across cancer samples, represent genomic positions with elevated mutation rates, often caused by highly localized mutational processes.We count the 11-mer genomic sequences across the genome, and using the PCAWG set of 2583 pan-cancer whole genomes, we associate 11-mers with mutational signatures, hotspots of single nucleotide variants, and specific genomic regions. We evaluate the mutation rates of individual and combined sets of 11-mers and derive mutational sequence motifs.We show that hotspots generally identify highly mutable sequence contexts. Using these, we show that some mutational signatures are enriched in hotspot sequence contexts, corresponding to well-defined sequence preferences for the underlying localized mutational processes. This includes signature 17b (of unknown etiology) and signatures 62 (POLE deficiency), 7a (UV), and 72 (linked to lymphomas). In some cases, the mutation rate and sequence preference increase further when focusing on certain genomic regions, such as signature 62 in transcribed regions, where the mutation rate is increased up to 9-folds over cancer type and mutational signature average.We summarize our findings in a catalog of localized mutational processes, their sequence preferences, and their estimated mutation rates.
Nucleosome assembly protein 1 like 1 (NAP1L1) promotes cardiac fibrosis by inhibiting YAP1 ubiquitination and degradation
Authors: Tianyu Li, Zhihui Niu, Tong Yu, Jinrui Li, Xin Lu, Mengqin Huang, Qianqian Wang, Xiaojiang Yu, Jiayue Feng, Bingqian Xu, Danyang Bing, Xuelian Li, Lifang Lu, Haihai Liang, Rui Yang, Bin Wang, Hongli Shan
Journal: MedComm (2023)

Myocardial fibrosis post myocardial infarction (MI) is characterized by abnormal extracellular matrix (ECM) deposition and cardiac dysfunction could finally develop into serious heart disease, like heart failure. Lots of regulating factors involved in this pathological process have been reported while the specific mediators and underlying mechanisms remain to need to be further investigated. As part of the NAP1 family, Nucleosome assembly protein 1 like 1 (NAP1L1) is expressed in a wide variety of tissues. Here, we report that NAP1L1 is a significant regulator of cardiac fibrosis and is upregulated in ischemic cardiomyopathy patient hearts. Enhanced expression of NAP1L1 can promote cardiac fibroblasts (CFs) proliferation, migration, and differentiation into myofibroblasts. In contrast, loss of NAP1L1 decreased fibrosis-related mRNA and protein levels, inhibited the trans-differentiation, and blunted migration and proliferation of CFs after Transforming Growth Factorβ1（TGF-β1）stimulation. In vivo, NAP1L1 knockout mice enhanced cardiac function and reduced fibrosis area in response to MI stimuli. Mechanically, NAP1L1 binding to Yes-associated protein 1 (YAP1) protein influences its stability, and silencing NAP1L1 can inhibit YAP1 expression by promoting its ubiquitination and degradation in CFs. Collectively, NAP1L1 could potentially be a new therapeutic target for various cardiac disorders, including myocardial fibrosis.
Can vitamins improve periodontal wound healing/regeneration?
Authors: Karim M. Fawzy El‐Sayed, Raluca Cosgarea, Anton Sculean, Christof Doerfer
Journal: Periodontology 2000 (2023)

Abstract Periodontitis is a complex inflammatory disorder of the tooth supporting structures, associated with microbial dysbiosis, and linked to a number if systemic conditions. Untreated it can result in an irreversible damage to the periodontal structures and eventually teeth loss. Regeneration of the lost periodontium requires an orchestration of a number of biological events on cellular and molecular level. In this context, a set of vitamins have been advocated, relying their beneficial physiological effects, to endorse the biological regenerative events of the periodontium on cellular and molecular levels. The aim of the present article is to elaborate on the question whether or not vitamins improve wound healing/regeneration, summarizing the current evidence from in vitro, animal and clinical studies, thereby shedding light on the knowledge gap in this field and highlighting future research needs. Although the present review demonstrates the current heterogeneity in the available evidence and knowledge gaps, findings suggest that vitamins, especially A, B, E, and CoQ 10 , as well as vitamin combinations, could exert positive attributes on the periodontal outcomes in adjunct to surgical or nonsurgical periodontal therapy.
Development and validation of a prognostic score to identify the optimal candidate for preemptive TIPS in patients with cirrhosis and acute variceal bleeding
Authors: Yong Lv, Wei Bai, Xuan Zhu, Hui Xue, Jianbo Zhao, Yuzheng Zhuge, Junhui Sun, Chunqing Zhang, Pengxu Ding, Zaibo Jiang, Xiaoli Zhu, Weixin Ren, Yingchun Li, Kewei Zhang, Wenguang Zhang, Kai Li, Zhengyu Wang, Bohan Luo, Xiaomei Li, Zhiping Yang, Wengang Guo, Dongdong Xia, Huahong Xie, Yanglin Pan, Zhanxin Yin, Daiming Fan, Guohong Han
Journal: Hepatology (2023)

Background and Aim: Baveno VII workshop recommends the use of preemptive TIPS (p-TIPS) in patients with cirrhosis and acute variceal bleeding (AVB) at high- risk of treatment failure. However, the criteria defining “high-risk” have low clinical accessibility or include subjective variables. We aimed to develop and externally validate a model for better identification of p-TIPS candidates. Approach and Results: The derivation cohort included 1554 patients with cirrhosis and AVB who were treated with endoscopy plus drug (n = 1264) or p-TIPS (n = 290) from 12 hospitals in China between 2010 and 2017. We first used competing risk regression to develop a score for predicting 6-week and 1-year mortality in patients treated with endoscopy plus drugs, which included age, albumin, bilirubin, international normalized ratio, white blood cell, creatinine, and sodium. The score was internally validated with the bootstrap method, which showed good discrimination (6 wk/1 y concordance-index: 0.766/0.740) and calibration, and outperformed other currently available models. In the second stage, the developed score was combined with treatment and their interaction term to predicate the treatment effect of p-TIPS (mortality risk difference between treatment groups) in the whole derivation cohort. The estimated treatment effect of p-TIPS varied substantially among patients. The prediction model had good discriminative ability (6 wk/1 y c -for-benefit: 0.696/0.665) and was well calibrated. These results were confirmed in the validation dataset of 445 patients with cirrhosis with AVB from 6 hospitals in China between 2017 and 2019 (6-wk/1-y c-for-benefit: 0.675/0.672). Conclusions: We developed and validated a clinical prediction model that can help to identify individuals who will benefit from p-TIPS, which may guide clinical decision-making.
CRISPR/Cas9-based application for cancer therapy: Challenges and solutions for non-viral delivery
Authors: Ying-Qi Lin, Ke-Ke Feng, Jie-Ying Lu, Jing-Qing Le, Wu-Lin Li, Bing-Chen Zhang, Cheng-Lei Li, Xun-Huan Song, Ling-Wu Tong, Jing-Wei Shao
Journal: Journal of Controlled Release (2023)
Hyodeoxycholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis
Authors: Junliang Kuang, Jieyi Wang, Yitao Li, Mengci Li, Mingliang Zhao, Kun Ge, Dan Zheng, Kenneth C.P. Cheung, Boya Liao, Shouli Wang, Tianlu Chen, Yinan Zhang, Congrong Wang, Guang Ji, Peng Chen, Hongwei Zhou, Cen Xie, Aihua Zhao, Weiping Jia, Xiaojiao Zheng, Wei Jia
Journal: Cell Metabolism (2023)

Non-alcoholic fatty liver disease (NAFLD) is regarded as a pandemic that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as distinct mechanistic pathways implicated in the development of NAFLD. Here, we report that a group of gut microbiota-modified bile acids (BAs), hyodeoxycholic acid (HDCA) species, are negatively correlated with the presence and severity of NAFLD. HDCA treatment has been shown to alleviate NAFLD in multiple mouse models by inhibiting intestinal farnesoid X receptor (FXR) and upregulating hepatic CYP7B1. Additionally, HDCA significantly increased abundances of probiotic species such as Parabacteroides distasonis, which enhances lipid catabolism through fatty acid-hepatic peroxisome proliferator-activated receptor alpha (PPARα) signaling, which in turn upregulates hepatic FXR. These findings suggest that HDCA has therapeutic potential for treating NAFLD, with a unique mechanism of simultaneously activating hepatic CYP7B1 and PPARα.
Targeting sphingosine 1-phosphate receptor 3 inhibits T-cell exhaustion and regulates recruitment of proinflammatory macrophages to improve antitumor efficacy of CAR-T cells against solid tumor
Authors: Ge Gao, Weiting Liao, Pei Shu, Qizhi Ma, Xia He, Benxia Zhang, Diyuan Qin, Yongsheng Wang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Backgrounds Chimeric antigen receptor (CAR)-modified T cells (CAR-T) are limited in solid tumors due to the hostile tumor microenvironment (TME). Combination therapy could be a promising approach to overcome this obstacle. Recent studies have shown that sphingosine 1-phosphate receptor (S1PR)3 has tremendous potential in regulating the immune environment. However, the functional significance of S1PR3 in T-cell-based immunotherapies and the molecular mechanisms have not been fully understood. Methods Here, we studied the combination of EpCAM-specific CAR T-cell therapy with pharmacological blockade of S1PR3 against solid tumor. We have applied RNA sequencing, flow cytometry, ELISA, cellular/molecular immunological technology, and mouse models of solid cancers. Results Our study provided evidence that S1PR3 high expression is positively associated with resistance to programmed cell death protein-1 (PD-1)-based immunotherapy and increased T-cell exhaustion. In addition, pharmacological inhibition of S1PR3 improves the efficacy of anti-PD-1 therapy. Next, we explored the possible combination of S1PR3 antagonist with murine EpCAM-targeted CAR-T cells in immunocompetent mouse models of breast cancer and colon cancer. The results indicated that the S1PR3 antagonist could significantly enhance the efficacy of murine EpCAM CAR-T cells in vitro and in vivo. Mechanistically, the S1PR3 antagonist improved CAR-T cell activation, regulated the central memory phenotype, and reduced CAR-T cell exhaustion in vitro. Targeting S1PR3 was shown to remodel the TME through the recruitment of proinflammatory macrophages by promoting macrophage activation and proinflammatory phenotype polarization, resulting in improved CAR-T cell infiltration and amplified recruitment of CD8+T cells. Conclusions This work demonstrated targeting S1PR3 could increase the antitumor activities of CAR-T cell therapy at least partially by inhibiting T-cell exhaustion and remodeling the TME through the recruitment of proinflammatory macrophages. These findings provided additional rationale for combining S1PR3 inhibitor with CAR-T cells for the treatment of solid tumor.
Towards Multiomics-Based Dissection of Anti-EGFR Sensitivity in Colorectal Cancer
Authors: Giovanni Randon, Filippo Pietrantonio
Journal: Clinical Cancer Research (2023)

Summary Overexpression of the EGFR ligands amphiregulin (AREG)/epiregulin (EREG) may be a surrogate of EGFR dependency regardless of sidedness in metastatic colorectal cancer. High AREG/EREG may be coupled with negative hyper-selection (i.e., lack of genomic drivers of primary resistance beyond RAS and BRAF) to identify patients with right-sided tumors and potential sensitivity to EGFR blockade. See related article by Williams et al., p. 4153
Baseline Dietary Patterns and Infertility Treatment Outcomes—Setting the Right Foundation
Authors: Antonia F. Oladipo, Tia Jackson-Bey
Journal: JAMA Network Open (2023)

Albert Salas-Huetos, MSc, PhD; Makiko Mitsunami, MD, MMSc; Siwen Wang, MD; Lidia Mínguez-Alarcón, PhD; Jordi Ribas-Maynou, PhD; Marc Yeste, PhD; Irene Souter, MD; Jorge E. Chavarro, MD, ScD; EARTH Study Team; Russ Hauser; Paige L Williams; Jorge E Chavarro; Lidia Minguez-Alarcon; Jennifer Ford; Myra Keller; Ramace Daad; Irene Souter; John Petrozza; Thomas L Toth; Diane L. Wright; Charles Bormann
Incident COVID-19 and Hospitalizations by Variant Era Among Vaccinated Solid Organ Transplant Recipients
Authors: Teresa Po-Yu Chiang, Aura T. Abedon, Jennifer L. Alejo, Dorry L. Segev, Allan B. Massie, William A. Werbel
Journal: JAMA Network Open (2023)

This cohort study evaluates the incidence of COVID-19 and hospitalizations across variant eras in 2021 and 2022 among vaccinated solid organ transplant (SOT) recipients.
Blocking Netrin-1 Slows Cancer Progression
Journal: Cancer Discovery (2023)

Abstract Preclinical and early clinical data demonstrate that treating endometrial cancer with the netrin-1 inhibitor NP137 helps arrest the epithelial-to-mesenchymal transition and disease progression. Additional research is needed to understand the mechanism of action between the monoclonal antibody and chemotherapy, as well as determine whether this treatment could help patients with other cancers.
Breastfeeding and the major fermentation metabolite lactate determine occurrence of <i>Peptostreptococcaceae</i> in infant feces
Authors: Lucía Huertas-Díaz, Rikke Kyhnau, Eugenio Ingribelli, Vera Neuzil-Bunesova, Qing Li, Mari Sasaki, Roger P. Lauener, Caroline Roduit, Remo Frei, CK-CARE Study Group, Ulrik Sundekilde, Clarissa Schwab
Journal: Gut Microbes (2023)

Previous studies indicated an intrinsic relationship between infant diet, intestinal microbiota composition and fermentation activity with a strong focus on the role of breastfeeding on microbiota composition. Yet, microbially formed short-chain fatty acids acetate, propionate and butyrate and other fermentation metabolites such as lactate not only act as substrate for bacterial cross-feeding and as mediators in microbe-host interactions but also confer antimicrobial activity, which has received considerably less attention in the past research. It was the aim of this study to investigate the nutritional-microbial interactions that contribute to the development of infant gut microbiota with a focus on human milk oligosaccharide (HMO) fermentation. Infant fecal microbiota composition, fermentation metabolites and milk composition were analyzed from 69 mother-infant pairs of the Swiss birth cohort Childhood AlleRgy nutrition and Environment (CARE) at three time points depending on breastfeeding status defined at the age of 4 months, using quantitative microbiota profiling, HPLC-RI and
Metal–Organic Framework for Hypoxia/ROS/pH Triple‐Responsive Cargo Release
Authors: Wenyu Chen, Huixin He, Pengfei Jiao, Lefei Han, Jianchun Li, Xiu Wang, Xuliang Guo
Journal: Advanced Healthcare Materials (2023)

Nanoparticulate antitumor photodynamic therapy (PDT) is suffering from a very short lifetime, limited diffusion distance of reactive oxygen species (ROS). Herein, a hypoxia/ROS/pH triple-responsive metal-organic framework (MOF) is designed to facilitate the on-demand release of photosensitizers and hence enhanced PDT efficacy. Tailored azo-containing imidazole ligand is coordinated with zinc to form MOF where photosensitizer (Chlorin e6/Ce6) is encapsulated. Azo can be reduced by overexpressed azoreductase in hypoxic tumor cells, resulting in depletion of glutathione (GSH) and thioredoxin (Trx) which are major antioxidants against ROS oxidative damage in PDT, resulting in rapid cargo release and additional efficacy amplification. The imidazole ionization causes a proton sponge effect to ensure the disintegration of the nanocarriers in acidic organelles, allowing the rapid release of Ce6 through lysosome escape. Under light irradiation, ROS produced by Ce6 may oxidize imidazole to urea, resulting in rapid cargo release. All of the triggers are expected to show interactive synergism. The pH- and hypoxia-responsiveness can improve the release rate of Ce6 for enhanced PDT therapy, whereas the consumption of oxygen by PDT may induce elevated hypoxia and hence in turn enhanced cargo release. This work highlights the role of triple-responsive nanocarriers for triggered photosensitizer release and improved antitumor PDT efficacy.
Correction: Inflammatory and tolerogenic myeloid cells determine outcome following human allergen challenge
Authors: Astrid L. Voskamp, Tamar Tak, Maarten L. Gerdes, Roberta Menafra, Ellen Duijster, Simon P. Jochems, Szymon M. Kielbasa, Tom Groot Kormelink, Koen A. Stam, Oscar R.J. van Hengel, Nicolette W. de Jong, Rudi W. Hendriks, Susan L. Kloet, Maria Yazdanbakhsh, Esther C. de Jong, Roy Gerth van Wijk, Hermelijn H. Smits
Journal: The Journal of Experimental Medicine (2023)
Perceptions of the Role of Living Alone in Providing Services to Patients With Cognitive Impairment
Authors: Elena Portacolone, Tung T. Nguyen, Barbara J. Bowers, Julene K. Johnson, Ashwin A. Kotwal, Robyn I. Stone, Sahru Keiser, Thi Tran, Elizabeth Rivera, Paula Martinez, Yulin Yang, Jacqueline M. Torres, Kenneth E. Covinsky
Journal: JAMA Network Open (2023)

Importance The potential role of living alone in either facilitating or hampering access to and use of services for older adults with cognitive impairment is largely unknown. Specifically, it is critical to understand directly from health care and social services professionals how living alone creates barriers to the access and use of supportive health care and social services for racially and ethnically diverse patients with cognitive impairment. Objective To identify the potential role of living alone in the access and use of health care and social services for diverse patients with cognitive impairment by investigating professionals’ perceptions of caring for such patients who live alone in comparison with counterparts living with others. Design, Setting, and Participants This qualitative study of 76 clinicians, social workers, and other professionals used semistructured interviews conducted between February 8, 2021, and June 8, 2022, with purposively sampled professionals providing services to diverse patients with cognitive impairment in Michigan, California, and Texas. Main Outcomes and Measures Clinicians, social workers, and other professionals compared serving patients with cognitive impairment and living alone vs counterparts living with others. An inductive content analysis was used to analyze the interview transcripts. Results A total of 76 professionals were interviewed (mean [SD] age, 49.3 [12.7] years); 59 were female (77.6%), 8 were Black or African American (11%), and 35 were White (46%). Participants included physicians, nurses, social workers, and home-care aides, for a total of 20 professions. Participants elucidated specific factors that made serving older adults living alone with cognitive impairment more challenging than serving counterparts living with others (eg, lacking an advocate, incomplete medical history, requiring difficult interventions), as well as factors associated with increased concerns when caring for older adults living alone with cognitive impairment, such as isolation and a crisis-dominated health care system. Participants also identified reasons for systematic unmet needs of older adults living alone with cognitive impairment for essential health care and social services, including policies limiting access and use to public home-care aides. Conclusions and Relevance In this qualitative study of professionals’ perspectives, findings suggest that living alone is a social determinant of health among patients with cognitive impairment owing to substantial barriers in access to services. Results raised considerable concerns about safety because the US health care system is not well equipped to address the unique needs of older adults living alone with cognitive impairment.